Explore the vast range of titles available.

Emicizumab, a factor (F)VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment for people with hemophilia A (PwHA). Although emicizumab is very potent, long-term outcomes from the clinical studies suggest that a small proportion of PwHA still experiences bleeds. Additionally, non-clinical studies indicate that the maximum cofactor activity of emicizumab is lower than international standard activity (100 IU/dL of FVIII). An increased cofactor activity BsAb would benefit such patients. Here, we report NXT007, a BsAb binding FIXa and FX developed through further engineering of emicizumab. Emicizumab has a common light chain, but through advances in antibody engineering, we were able to create a more potent BsAb with two new non-common light chains. After extensive optimization of the heavy and light chains, the resulting BsAb, NXT007, exerted in vitro thrombin generation (TG) activity in hemophilia A plasma equivalent to 100 IU/dL of FVIII when triggered by tissue factor. NXT007 demonstrated potent hemostatic activity in an acquired hemophilia A model in non-human primates at a much lower dosage than emicizumab, consistent with an around 30-fold dose shift in the in vitro TG activity between NXT007 and emicizumab. Moreover, together with Fc engineering that enhanced FcRn binding and reduced in vivo clearance, we demonstrate that NXT007 could be effective at a much lower dosage with a longer dosing interval compared to emicizumab. These non-clinical results suggest that NXT007 could maintain a non-hemophilic range of coagulation potential in PwHA and provides a rationale for its clinical testing.

Emicizumab, a factor (F)VIIIa-function mimetic therapeutic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment for people with hemophilia A (PwHA). However, non-clinical studies suggest that the maximum cofactor activity of emicizumab is lower than international standard activity (100 IU/dL of FVIII), leaving room for further improvement. Since not all PwHA experienced zero treated bleeds, increased cofactor activity would be beneficial for such patients. Here, we report NXT007, a BsAb against FIXa and FX developed through further engineering of emicizumab. While emicizumab has a common light chain, advances in antibody engineering enabled us to identify a more potent BsAb with two distinct new light chains, and following extensive mutational optimization of the two emicizumab-derived heavy chains and two light chains, the resulting NXT007 exerted in vitro thrombin generation (TG) activity in hemophilia A plasma corresponding to that at 100 IU/dL of FVIII when coagulation is triggered by tissue factor. NXT007 demonstrated potent hemostatic activity in an acquired hemophilia A model in non-human primates at much lower dosage than emicizumab, consistent with an around 30-fold dose shift in the in vitro TG activity between NXT007 and emicizumab. Moreover, together with Fc engineering that enhanced FcRn binding and reduced in vivo clearance, we demonstrate that NXT007 could be effective at much lower dosage with a longer dosing interval compared to emicizumab. These non-clinical results suggest that NXT007 is expected to maintain a non-hemophilic range of coagulation potential in PwHA and provides a rationale for its clinical testing.Competing Interest StatementThe authors have declared no competing interest.

When assessing patients with depressive and anxiety disorders in psychiatric clinical practice, it is common to encounter children and adolescents who have experienced abuse and victimization. To date, it has been clarified that experiences of \"childhood abuse\" and \"childhood victimization\" lead to \"neuroticism\", and that neuroticism leads to \"adult depressive symptoms\". In this study, we analyzed how these four factors are interrelated. The following self-administered questionnaire surveys were conducted in 576 adult volunteers: Patient Health Questionnaire-9, Eysenck Personality Questionnaire-revised shortened version, Child Abuse and Trauma Scale, and Childhood Victimization Rating Scale. For statistical analysis, Pearson correlation coefficient analysis, -test, multiple regression analysis, and covariance structure analysis (path analysis) were performed. Path analysis showed that the indirect effects of childhood abuse and childhood victimization on depressive symptoms through neuroticism were statistically significant. In addition, the indirect effects of childhood abuse on neuroticism through childhood victimization were statistically significant. Finally, the indirect effects of childhood abuse on depressive symptoms through the combined paths of childhood victimization and neuroticism were statistically significant. Our results suggest that \"childhood abuse (A)\" induces changes in the personality trait of \"neuroticism (C)\" with \"childhood victimization (B)\" as a mediator, and that these adversities affect the expression of \"depressive symptoms in adulthood (D)\" through \"neuroticism (C)\" as a mediator. In other words, to our knowledge, this is the first study to clarify that these four factors are not only individually associated with each other but also cause a chain reaction of A to B to C to D.

Background: Previous studies have reported that physical activity can prevent the onset of depression and reduces anxiety. In the present study, the hypothesis that total physical activity time influences depressive symptoms via state and trait anxiety was tested by a path analysis. Methods: Self-administered questionnaires were used to survey 526 general adult volunteers from April 2017 to April 2018. Demographic information, physical activity, and state and trait anxiety were investigated. Results: The association between physical activity time and depressive symptoms was expressed as a U-shape curve. The results of the covariance structure analysis showed that differences from the optimal physical activity time (DOT) had direct positive effects on state and trait anxiety. DOT affected depressive symptoms only via trait anxiety, and this was a complete mediation model. Conclusion: The present study suggests that an optimal physical activity time exists for depressive symptoms. The path model demonstrated an association between the three factors of optimal physical activity time, trait anxiety, and depressive symptoms, and the effect was fully mediated by trait anxiety.

An isometric virus was isolated from a cultivated Adonis plant ( A. ramosa ). The purified virus particle is 28 nm in diameter and is composed of a single coat protein and a single RNA genome of 3,991 nucleotides. Sequence analysis showed that the virus is closely related to carnation mottle virus. The virus was used to mechanically infect healthy A. ramosa plants, resulting in mosaic and leaf curl symptoms; however, attempts to inoculate carnation plants did not result in infection. We propose the virus as a new carmovirus and have named it adonis mosaic virus (AdMV).

Background: Personality traits, such as neuroticism, that results in vulnerability to stress, and resilience, a measure of stress coping, are closely associated with the onset of depressive symptoms, whereas regular physical activity habits have been shown to reduce depressive symptoms. In this study, the mediating effects of neuroticism and resilience between physical activity duration and depressive symptoms were investigated by a covariance structure analysis. Methods: Between April 2017 and April 2018, 526 adult volunteers were surveyed using self-administered questionnaires. Demographic information, habitual physical activity duration (PAD), neuroticism, and resilience were investigated. The effects of these factors on depressive symptoms were analyzed by a covariance structure analysis. This study was conducted with the approval of the Medical Ethics Committee of Tokyo Medical University. Results: The dose–response curves of physical activity duration and depression scores were U-shaped: the optimal physical activity duration for the lowest depression score was 25.7 h/week. We found that the greater the difference from the optimal PAD, the higher the neuroticism and the lower the resilience, and the more severe the depressive symptoms. Covariance structure analysis demonstrated that neuroticism and resilience significantly and completely mediated the effects of the difference from the optimal PAD on depressive symptoms (coefficient of determination R2 = 0.349). Conclusion: Our study suggests that there is an optimal PAD that reduces depressive symptoms, and that a greater difference from the optimal PAD increases depressive symptoms through neuroticism and resilience.